Much has been expected from tumor necrosing factor (hereinafter abbreviated as TNF) since its discovery as an anti-tumor drug, because of its in vivo activity of causing hemorrhagic necrosis of various tumors without seriously affecting normal tissue cells, and also its in virgo activity of killing various tumor cells directly or inhibiting their growth. Pennica, et al [Nature 312, 724-728 (1984)] isolated cDNA of human TNF, determined the amino acid sequence of human TNF, and reported its expression in Escherichia coli [hereinafter, the polypeptide having an amino acid sequence of human TNF found by Pennica, et al. is abbreviated as h-TNF (N1)]. It is well known that similar reports were subsequently made by other groups. Now that it is possible to obtain a highly purified TNF standard substance by DNA recombinant technology, studies on the biological activities of TNF have been actively conducted. As a result, it has been revealed that TNF has, in addition to its known anti-tumor activity (tumoricidal activity and cytotoxic activity on hemangioendothelium), a wide variety of biological activities. Such biological activities include: 1) the activity of promoting growth of fibroblast cells; 2) the activation of leukocytes; 3) the activity of increasing the production of various cytokins (interleukin 1, interferon .beta..sub.2, colony-stimulating factor); 4) the activity of increasing the production of prostaglandin E.sub.2 and collagenase; 5) the activity of increasing the production of various membrane proteins; 6) the activity of increasing the absorption of bone and cartilage; and 7) differentiation-inducing activity.
As described above, it has been revealed that TNF possesses a wide variety of biological activities. Recently, Cerami, et al. pointed out an important factor in the clinical application of TNF as an anti-tumor agent. That is, Cerami, et al. found that, in the process of studying cachectin which is a causative agent of cachectic effects observed in serious or chronic infections or in cancer patients, TNF and cachectin are in fact identical substances [Beutler, et al., Nature, 316, 552-554 (1985)]. This fact implies that if TNF per se is applied clinically as an anti-tumor agent, a serious adverse effect (cachectic effect) will accompany it. At present, therefore, the development of TNF derivatives which have reduced cachectic effect is highly desirable.